WO2016144848A1 - Inhibiteurs de pyrrolotriazine de l'activité d'irak4 - Google Patents

Inhibiteurs de pyrrolotriazine de l'activité d'irak4 Download PDF

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Publication number
WO2016144848A1
WO2016144848A1 PCT/US2016/021124 US2016021124W WO2016144848A1 WO 2016144848 A1 WO2016144848 A1 WO 2016144848A1 US 2016021124 W US2016021124 W US 2016021124W WO 2016144848 A1 WO2016144848 A1 WO 2016144848A1
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Prior art keywords
triazine
carboxamide
pyrrolo
methyl
pyrazol
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PCT/US2016/021124
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English (en)
Inventor
Jongwon Lim
Michael D. Altman
Jason D. Brubaker
Craig R. Gibeau
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Merck Sharp & Dohme Corp.
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Priority to EP16762278.6A priority Critical patent/EP3268006B1/fr
Priority to US15/557,203 priority patent/US10329295B2/en
Publication of WO2016144848A1 publication Critical patent/WO2016144848A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings

Definitions

  • the present invention is directed to compounds which modulate interleukin-1 (IL-1)
  • IRAK4 receptor-associated kinase 4
  • cytokines appear to play key roles in these processes, particularly IL-1 and TNF. Both cytokines are derived from mononuclear cells and macrophages, along with other cell types. Physiologically, they produce many of the same proinflammatory responses, including fever, sleep and anorexia, mobilization and activation of polymorphonuclear leukocytes, induction of cyclooxygenase and lipoxygenase enzymes, increase in adhesion molecule expression, activation of B-cells, T-cells and natural killer cells, and stimulation of production of other cytokines. Other actions include a
  • cytokines play key roles in a large number of pathological conditions, including rheumatoid arthritis, inflammatory bowel disease, multiple sclerosis, diabetes, obesity, cancer, sepsis, etc.
  • IL-1 receptor antagonist protein IL-IRa or IRAP
  • Dinarello Cytokine Growth Factor Rev., 1997, 8:253-265.
  • IL-1 treatment of cells induces the formation of a complex consisting of the two IL-1 receptor chains, IL-1R1 and IL-lRAcP, and the resulting heterodimer recruits an adaptor molecule designated as MyD88.
  • MyD88 binds to a protein designated IRAK (IL-1 receptor associated kinase).
  • IRAK IL-1 receptor associated kinase
  • IRAK is subsequently phosphorylated and released from the receptor complex to interact with a tumor necrosis factor receptor-associated factor, TRAF6, which transduces the signal to downstream effector molecules.
  • TRAF6 can trigger the NIK/IKK kinase cascade to activate the transcription factor NK-kappa B.
  • NF-kappa B regulates a number of genes that, in rum, regulate immune and inflammatory responses.
  • IRAKI see, e.g., Cao et al, Science, 1996.
  • IRAK2 see, e.g. Muzio et al, Science, 1997, 278: 1612-1615
  • IRAK3 monomyeloic cell specific IRAKM
  • IRAK4 see, e.g., PCT Publication No. WO 01/051641.
  • IRAK proteins have been shown to play a role in transducing signals other than those originating from IL-1 receptors, including signals triggered by activation of IL-18 receptors (see, e.g., Kanakaraj et al, J. Exp. Med., 1999, 189(7): 1129-1138) and LPS receptors (see, e.g., Yang et al, J.
  • compositions that comprise the novel compounds that are inhibitors of IRAK4.
  • the present invention relates to pyrrolotriazine inhibitors of IRAK4 of formula (I) and provides compositions comprising such inhibitors, as well as methods therewith for treating IRAK4-mediated or -associated conditions or diseases.
  • the compounds of the instant invention are useful in the inhibition of the activity of IRAK4.
  • Ring A is aryl or heterocyclyl
  • n 0, 1, 2, 3 or 4;
  • Ri is independently selected from: (Ci-C4)alkyl, (C3-C6)cycloalkyl, heterocyclyl, CF 3 , CHF 2 , CN, halo, said alkyl, cycloalkyl and heterocyclyl optionally substituted with halo, OH, CH 3 , and OCH 3 ;
  • R2 is H and R 3 is independently selected from: (Ci-C6)alkyl, (C 3 -Cg)cycloalkyl and heterocyclyl each optionally substituted with one or more halo, OH, N(R ) 2 , or morpholinyl, or R 2 and R 3 can be taken together with the nitrogen to which they are attached to form a heterocyclyl, said heterocyclyl optionally substituted with one or more substituents selected from
  • R a is independently selected from (Ci-C4)alkyl, (C 3 -C6)cycloalkyl, CF 3 , CHF 2 , OH, halo and NH 2 , said alkyl optionally substituted with (C 3 -Ce)cycloalkyl and CF 3 ; and
  • Rb is independently selected from H and (Ci-C4)alkyl
  • Ring A is pyrazolyl, pyridinyl, thiophenyl, furanyl or phenyl;
  • n 0, 1 or 2;
  • Ri is independently selected from: (Ci-C4)alkyl, cyclopropyl, oxadiazolyl, pyridinyl, oxazolyl, triazolyl, pyriminidyl, CF 3 , CHF 2 , CN and halo, said alkyl, oxadiazolyl, pyridinyl, oxazolyl, triazolyl and pyriminidyl are optionally substituted with halo, OH, CH 3 , and OCH 3 ;
  • R 2 is H and R 3 is independently selected from: (Ci-C4)alkyl, cyclohexyl, cycloheptyl, piperidinyl and azepanyl each optionally substituted with one or more F, OH,
  • N(R b ) 2 , or morpholinyl, or R 2 and R 3 can be taken together with the nitrogen to which they are attached to form a heterocyclyl selected from piperazinyl, diazepanyl, diazabicyclooctyl, diazabicycloheptyl, diazaspirononyl, hexahydropyrrolopyrazinyl, piperidinyl, diazabicyclononyl, oxadiazabicyclodecyl and diazatricyclodecyl, said heterocyclyl optionally substituted with one or more substituents selected from R a ;
  • R a is independently selected from (Ci-C4)alkyl, cyclopropyl, CF 3 , CHF 2 , OH, F and NH 2 , said alkyl optionally substituted with cyclopropyl and CF 3 ; and
  • R b is independently selected from H and methyl
  • any variable e.g. R a , etc.
  • its definition on each occurrence is independent at every other occurrence.
  • combinations of substituents and variables are permissible only if such combinations result in stable compounds.
  • Lines drawn into the ring systems from substituents represent that the indicated bond may be attached to any of the substitutable ring atoms. If the ring system is bicyclic, it is intended that the bond be attached to any of the suitable atoms on either ring of the bicyclic moiety.
  • one or more silicon (Si) atoms can be incorporated into the compounds of the instant invention in place of one or more carbon atoms by one of ordinary skill in the art to provide compounds that are chemically stable and that can be readily synthesized by techniques known in the art from readily available starting materials.
  • Carbon and silicon differ in their covalent radius leading to differences in bond distance and the steric arrangement when comparing analogous C-element and Si-element bonds. These differences lead to subtle changes in the size and shape of silicon-containing compounds when compared to carbon.
  • size and shape differences can lead to subtle or dramatic changes in potency, solubility, lack of off target activity, packaging properties, and so on.
  • substituents and substitution patterns on the compounds of the instant invention can be selected by one of ordinary skill in the art to provide compounds that are chemically stable and that can be readily synthesized by techniques known in the art, as well as those methods set forth below, from readily available starting materials. If a substituent is itself substituted with more than one group, it is understood that these multiple groups may be on the same carbon or on different carbons, so long as a stable structure results. In some instances, two substituents are attached to the same carbon and come together to form a carbocyclic or heterocyclic ring (a spirocyclic ring system).
  • alkyl is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms.
  • C1-C6, as in “(Ci-C6)alkyl” is defined to include groups having 1, 2, 3, 4, 5 or 6 carbons in a linear or branched arrangement.
  • (Ci-C6)alkyl” specifically includes methyl, ethyl, ⁇ -propyl, z-propyl, w-butyl, /-butyl, z-butyl, pentyl, hexyl, and so on.
  • C1-C4, as in “(Ci-C4)alkyl” is defined to include groups having 1, 2, 3 or 4 carbons in a linear or branched arrangement.
  • “(Ci-C4)alkyl” specifically includes methyl, ethyl, n- propyl, z-propyl, z?-butyl, /-butyl and z-butyl.
  • cycloalkyl means a monocyclic saturated aliphatic hydrocarbon group having the specified number of carbon atoms.
  • cycloalkyl includes cyclopropyl, methyl-cyclopropyl, 2,2-dimethyl-cyclobutyl, 2-ethyl-cyclopentyl, cyclohexyl, and so on.
  • aryl is intended to mean any stable monocyclic or bicyclic carbon ring of up to 7 atoms in each ring, wherein at least one ring is aromatic.
  • aryl elements include phenyl, naphthyl, tetrahydro-naphthyl, indanyl and biphenyl.
  • the aryl substituent is bicyclic and one ring is non-aromatic, it is understood that attachment is via the aromatic ring.
  • heterocycle or “heterocyclyl” as used herein is intended to mean a 3- to 10-membered aromatic or nonaromatic heterocycle containing from 1 to 4 heteroatoms selected from the group consisting of O, N and S, and includes spiro, bicyclic and tricyclic groups. "Heterocyclyl” therefore includes heteroaryls, as well as dihydro and tetrathydro analogs thereof.
  • heterocyclyl include, but are not limited to the following: benzoimidazolyl, benzoimidazolonyl, benzofuranyl, benzofurazanyl, benzopyrazolyl, benzotriazolyl, benzothiophenyl, benzoxazolyl, carbazolyl, carbolinyl, cinnolinyl, furanyl, imidazolyl, indolinyl, indolyl, indolazinyl, indazolyl, isobenzofuranyl, isoindolyl, isoquinolyl, isothiazolyl, isoxazolyl, naphthpyridinyl, oxadiazolyl, oxazolyl, oxazoline, isoxazoline, oxetanyl, pyranyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridopyridinyl,
  • dihydrobenzoimidazolyl dihydrobenzofuranyl, dihydrobenzothiophenyl, dihydrobenzoxazolyl, dihydrofuranyl, dihydroimidazolyl, dihydroindolyl, dihydroisooxazolyl, dihydroisothiazolyl, dihydrooxadiazolyl, dihydrooxazolyl, dihydropyrazinyl, dihydropyrazolyl, dihydropyridinyl, dihydropyrimidinyl, dihydropyrrolyl, dihydroquinolinyl, dihydrotetrazolyl, dihydrothiadiazolyl, dihydrothiazolyl, dihydrothienyl, dihydrotriazolyl, dihydroazetidinyl, methylenedioxybenzoyl, tetrahydrofuranyl, and tetrahydrothienyl, and N-oxides thereof. Attachment of
  • halo or halogen as used herein is intended to include chloro (CI), fluoro (F), bromo (Br) and iodo (I).
  • the compounds of this invention include the salts, solvates, hydrates or prodrugs of the compounds.
  • the use of the terms “salt”, “solvate”, “hydrate”, “prodrug” and the like, is intended to equally apply to the salt, solvate, hydrate and prodrug of enantiomers, stereoisomers, rotamers, tautomers, positional isomers, or racemates of the inventive compounds.
  • the IRAK4 inhibitor compounds of the present invention which can be in the form of a free base, may be isolated from the reaction mixture in the form of a pharmaceutically acceptable salt.
  • the compounds of Formula I can form salts which are also within the scope of this invention.
  • Reference to a compound of Formula I herein is understood to include reference to pharmaceutically acceptable salts thereof, unless otherwise indicated.
  • salt(s) denotes acidic salts formed with inorganic and/or organic acids, as well as basic salts formed with inorganic and/or organic bases.
  • a compound of Formula I contains both a basic moiety, such as, but not limited to a pyridine or imidazole, and an acidic moiety, such as, but not limited to a carboxylic acid, zwitterions ("inner salts") may be formed and are included within the term “salt(s)" as used herein.
  • Such acidic and basic salts used within the scope of the invention are pharmaceutically acceptable (i.e., non-toxic, physiologically acceptable) salts.
  • Salts of the compounds of Formula I may be formed, for example, by reacting a compound of Formula I with an amount of acid or base, such as an equivalent amount, in a medium such as one in which the salt precipitates or in an aqueous medium followed by lyophilization.
  • Exemplary acid addition salts include acetates, ascorbates, benzoates, benzenesulfonates, bisulfates, borates, butyrates, citrates, camphorates, camphorsulfonates, fumarates, hydrochlorides, hydrobromides, hydroiodides, lactates, maleates, methanesulfonates, naphthalenesulfonates, nitrates, oxalates, phosphates, propionates, salicylates, succinates, sulfates, tartarates, thiocyanates, toluenesulfonates (also known as tosylates,) and the like.
  • Exemplary basic salts include ammonium salts, alkali metal salts such as sodium, lithium, and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases (for example, organic amines) such as dicyclohexylamines, t-butyl amines, and salts with amino acids such as arginine, lysine and the like.
  • alkali metal salts such as sodium, lithium, and potassium salts
  • alkaline earth metal salts such as calcium and magnesium salts
  • salts with organic bases for example, organic amines
  • organic amines such as dicyclohexylamines, t-butyl amines
  • salts with amino acids such as arginine, lysine and the like.
  • Basic nitrogen- containing groups may be quarternized with agents such as lower alkyl halides (e.g., methyl, ethyl, and butyl chlorides, bromides and iodides), dialkyl sulfates (e.g., dimethyl, diethyl, and dibutyl sulfates), long chain halides (e.g., decyl, lauryl, and stearyl chlorides, bromides and iodides), aralkyl halides (e.g., benzyl and phenethyl bromides), and others.
  • lower alkyl halides e.g., methyl, ethyl, and butyl chlorides, bromides and iodides
  • dialkyl sulfates e.g., dimethyl, diethyl, and dibutyl sulfates
  • long chain halides e.g., decyl, lauryl, and
  • the IRAK4 inhibitor compounds of the present invention may exist as amorphous forms or crystalline forms.
  • the compounds of Formula I may have the ability to crystallize in more than one form, a characteristic known as polymorphism, and it is understood that such polymorphic forms (“polymorphs”) are within the scope of Formula I.
  • Polymorphism generally can occur as a response to changes in temperature or pressure or both and can also result from variations in the crystallization process.
  • Polymorphs can be distinguished by various physical characteristics known in the art such as x-ray diffraction patterns, solubility and melting point.
  • the compounds having Formula I or the pharmaceutically acceptable salts may form hydrates or solvates. It is known to those of skill in the art that charged compounds form hydrated species when lyophilized with water, or form solvated species when concentrated in a solution with an appropriate organic solvent.
  • the compounds of this invention include the hydrates or solvates of the compounds listed.
  • One or more compounds of the invention having Formula I or the pharmaceutically acceptable salts or solvates thereof may exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like, and it is intended that the invention embrace both solvated and unsolvated forms.
  • “Solvate” means a physical association of a compound of this invention with one or more solvent molecules. This physical association involves varying degrees of ionic and covalent bonding, including hydrogen bonding. In certain instances the solvate will be capable of isolation, for example when one or more solvent molecules are incorporated in the crystal lattice of the crystalline solid. "Solvate” encompasses both solution-phase and isolatable solvates. Non-limiting examples of suitable solvates include ethanolates, methanolates, and the like.
  • “Hydrate” is a solvate wherein the solvent molecule is H 2 0.
  • a typical, non-limiting, process involves dissolving the inventive compound in desired amounts of the desired solvent (organic or water or mixtures thereof) at a higher than ambient temperature, and cooling the solution at a rate sufficient to form crystals which are then isolated by standard methods.
  • Analytical techniques such as, for example IR spectroscopy, show the presence of the solvent (or water) in the crystals as a solvate (or hydrate).
  • the compounds of Formula I may contain asymmetric or chiral centers, and, therefore, exist in different stereoisomeric forms. It is intended that all stereoisomeric forms of the compounds of Formula I, as well as mixtures thereof, including racemic mixtures, form part of the present invention.
  • the present invention embraces all geometric and positional isomers. For example, if a compound of Formula I incorporates a double bond or a fused ring, both the cis- and trans-forms, as well as mixtures, are embraced within the scope of the invention.
  • Such stereoisomeric forms also include enantiomers and diastereoisomers, etc.
  • chiral compounds For chiral compounds, methods for asymmetric synthesis whereby the pure stereoisomers are obtained are well known in the art, e.g. synthesis with chiral induction, synthesis starting from chiral intermediates, enantioselective enzymatic conversions, separation of stereoisomers using chromatography on chiral media. Such methods are described in Chirality in Industry (edited by A.N. Collins, G.N. Sheldrake and J. Crosby, 1992; John Wiley). Likewise methods for synthesis of geometrical isomers are also well known in the art.
  • Diastereomeric mixtures can be separated into their individual diastereomers on the basis of their physical chemical differences by methods well known to those skilled in the art, such as, for example, by chromatography and/or fractional crystallization.
  • Enantiomers can be separated by converting the enantiomeric mixture into a diastereomeric mixture by reaction with an appropriate optically active compound (e.g. chiral auxiliary such as a chiral alcohol or Mosher's acid chloride), separating the diastereomers and converting (e.g. hydrolyzing) the individual diastereomers to the corresponding pure enantiomers.
  • an appropriate optically active compound e.g. chiral auxiliary such as a chiral alcohol or Mosher's acid chloride
  • some of the compounds of Formula I may be atropisomers (e.g. substituted biaryls) and are considered as part of this invention.
  • Enantiomers can also be separated by use of chiral HPLC column.
  • All stereoisomers for example, geometric isomers, optical isomers and the like
  • of the present compounds including those of the salts, solvates, esters and prodrugs of the compounds as well as the salts, solvates and esters of the prodrugs, such as those which may exist due to asymmetric carbons on various substituents, including enantiomeric forms (which may exist even in the absence of asymmetric carbons), rotameric forms, atropisomers, and diastereomeric forms, are contemplated within the scope of this invention, as are positional isomers.
  • Individual stereoisomers of the compounds of the invention may, for example, be substantially free of other isomers, or may be admixed, for example, as racemates or with all other, or other selected, stereoisomers.
  • the chiral centers of the present invention can have the S or R configuration as defined by the IUPAC 1974 Recommendations. The use of the terms
  • salt “salt”, “solvate”, “ester”, “prodrug” and the like, is intended to equally apply to the salt, solvate, ester and prodrug of enantiomers, stereoisomers, rotamers, tautomers, positional isomers, racemates or prodrugs of the inventive compounds.
  • prodrug means a compound (e.g, a drug precursor) that is transformed in vivo to yield a compound of Formula I or a pharmaceutically acceptable salt, hydrate or solvate of the compound. The transformation may occur by various mechanisms (e.g. by metabolic or chemical processes), such as, for example, through hydrolysis in blood.
  • prodrugs are provided by T. Higuchi and W. Stella, "Pro-drugs as Novel Delivery Systems," Vol. 14 of the A.C.S. Symposium Series, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987.
  • the atoms may exhibit their natural isotopic abundances, or one or more of the atoms may be artificially enriched in a particular isotope having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number predominantly found in nature.
  • the present invention is meant to include all suitable isotopic variations of the compounds of generic Formula I.
  • different isotopic forms of hydrogen (H) include protium (TT) and deuterium ( 2 H).
  • TT protium
  • 2 H deuterium
  • Protium is the predominant hydrogen isotope found in nature.
  • Enriching for deuterium may afford certain therapeutic advantages, such as increasing in vivo half-life or reducing dosage requirements, or may provide a compound useful as a standard for characterization of biological samples.
  • Isotopically-enriched compounds within generic Formula I can be prepared without undue experimentation by conventional techniques well known to those skilled in the art or by processes analogous to those described in the Schemes and Examples herein using appropriate isotopically-enriched reagents and/or intermediates.
  • Certain isotopically -labelled compounds of Formula I are useful in compound and/or substrate tissue distribution assays. Tritiated (i.e., H) and carbon-14 (i.e., 14 C) isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium (i.e., 2 H) may afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and hence may be preferred in some circumstances.
  • Isotopically labelled compounds of Formula I can generally be prepared by following procedures analogous to those disclosed in the Schemes and/or in the Examples herinbelow, by substituting an appropriate isotopically labeled reagent for a non-isotopically labeled reagent.
  • the present invention provides a method of treating or reducing the severity of a disease in a patient by using a compound of Formulas I as described above, wherein said disease is selected from IRAK4 mediated pathologies, such as rheumatoid arthritis, multiple sclerosis, sepsis, osteoarthritis, inflammatory bowel disease, Parkinson's disease, cardiac contractile dysfunction, type I diabetes, type II diabetes or familial cold autoinflammatory syndrome, allergic disease, cancer, lupus, psoriasis, asthma or graft rejection.
  • IRAK4 mediated pathologies such as rheumatoid arthritis, multiple sclerosis, sepsis, osteoarthritis, inflammatory bowel disease, Parkinson's disease, cardiac contractile dysfunction, type I diabetes, type II diabetes or familial cold autoinflammatory syndrome, allergic disease, cancer, lupus, psoriasis, asthma or graft rejection.
  • the kinase activity of IRAK4 may be modulated in a variety of ways; that is, one can affect the phosphorylation/activation of IRAK4 either by modulating the initial phosphorylation of the protein or by modulating the autophosphorylation of the other active sites of the protein.
  • the kinase activity of IRAK4 may be modulated by affecting the binding of a substrate of IRAK4 phosphorylation.
  • the compounds of the invention are used to treat or prevent inflammation related diseases.
  • Disease states which can be treated by the methods and compositions provided herein include, but are not limited to, cancer, autoimmune disease, viral disease, fungal disease, neurological/neurodegenerative disorders, arthritis, inflammation, anti-proliferative (e.g. ocular retinopathy), neuronal, alopecia, cardiovascular disease, graft rejection, inflammatory bowel disease, proliferation induced after medical procedures, including, but not limited to, surgery, angioplasty, and the like. It is appreciated that in some cases the cells may not be in a hyper- or hypoproliferation state (abnormal state) and still require treatment. Thus, in one embodiment, the invention herein includes application to cells or individuals which are afflicted or may eventually become afflicted with any one of these disorders or states.
  • the compounds of this invention may be administered to mammals, including humans, either alone or, in combination with pharmaceutically acceptable carriers, excipients or diluents, in a pharmaceutical composition, according to standard pharmaceutical practice.
  • the compounds can be administered orally or parenterally, including the intravenous, intramuscular, intraperitoneal, subcutaneous and topical routes of administration.
  • compositions containing the active ingredient may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs.
  • compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations.
  • Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients may be for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example,
  • the tablets may be uncoated or they may be coated by known techniques to mask the unpleasant taste of the drug or delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.
  • a water soluble taste masking material such as hydroxypropylmethyl-cellulose or hydroxypropylcellulose, or a time delay material such as ethyl cellulose, cellulose acetate buryrate may be employed.
  • Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water soluble carrier such as poly ethylenegly col or an oil medium, for example peanut oil, liquid paraffin, or olive oil.
  • an inert solid diluent for example, calcium carbonate, calcium phosphate or kaolin
  • water soluble carrier such as poly ethylenegly col or an oil medium, for example peanut oil, liquid paraffin, or olive oil.
  • Aqueous suspensions contain the active material in admixture with excipients suitable for the manufacture of aqueous suspensions.
  • excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethyl-cellulose, sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally-occurring phosphatide, for example lecithin, or condensation products of an alkylene oxide with fatty acids, for example poly oxy ethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethylene- oxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as poly oxy ethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene
  • the aqueous suspensions may also contain one or more preservatives, for example ethyl, or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose, saccharin or aspartame.
  • preservatives for example ethyl, or n-propyl p-hydroxybenzoate
  • coloring agents for example ethyl, or n-propyl p-hydroxybenzoate
  • flavoring agents such as sucrose, saccharin or aspartame.
  • sweetening agents such as sucrose, saccharin or aspartame.
  • Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in mineral oil such as liquid paraffin.
  • the oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol.
  • Sweetening agents such as those set forth above, and flavoring agents may be added to provide a palatable oral preparation.
  • These compositions may be preserved by the addition of an anti-oxidant such as butylated hydroxyanisol or alpha-tocopherol.
  • Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives.
  • Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example sweetening, flavoring and coloring agents, may also be present. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.
  • the pharmaceutical compositions of the invention may also be in the form of an oil-in-water emulsion.
  • the oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin or mixtures of these.
  • Suitable emulsifying agents may be naturally-occurring phosphatides, for example soy bean lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, for example sorbitan monooleate, and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate.
  • the emulsions may also contain sweetening, flavouring agents, preservatives and antioxidants.
  • Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative, flavoring and coloring agents and antioxidant.
  • sweetening agents for example glycerol, propylene glycol, sorbitol or sucrose.
  • Such formulations may also contain a demulcent, a preservative, flavoring and coloring agents and antioxidant.
  • compositions may be in the form of sterile injectable aqueous solutions.
  • acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution.
  • the sterile injectable preparation may also be a sterile injectable oil-in-water microemulsion where the active ingredient is dissolved in the oily phase.
  • the active ingredient may be first dissolved in a mixture of soybean oil and lecithin. The oil solution then introduced into a water and glycerol mixture and processed to form a microemulsion.
  • the injectable solutions or microemulsions may be introduced into a patient's blood-stream by local bolus injection.
  • a continuous intravenous delivery device may be utilized.
  • An example of such a device is the Deltec CADD- PLUSTM model 5400 intravenous pump.
  • the pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleagenous suspension for intramuscular and subcutaneous administration.
  • This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally- acceptable diluent or solvent, for example as a solution in 1,3-butane diol.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil may be employed including synthetic mono- or diglycerides.
  • fatty acids such as oleic acid find use in the preparation of injectables.
  • topical use creams, ointments, jellies, solutions or suspensions, etc., containing the compound of Formula I are employed. (For purposes of this application, topical application shall include mouth washes and gargles.)
  • the compounds for the present invention can be administered in intranasal form via topical use of suitable intranasal vehicles and delivery devices, or via transdermal routes, using those forms of transdermal skin patches well known to those of ordinary skill in the art.
  • the dosage administration will, of course, be continuous rather than intermittent throughout the dosage regimen.
  • Compounds of the present invention may also be delivered as a suppository employing bases such as cocoa butter, glycerinated gelatin, hydrogenated vegetable oils, mixtures of polyethylene glycols of various molecular weights and fatty acid esters of polyethylene glycol.
  • the daily dosage will normally be determined by the prescribing physician with the dosage generally varying according to the age, weight, and response of the individual patient, as well as the severity of the patient's symptoms.
  • the dosage regimen utilizing the compounds of the instant invention can be selected in accordance with a variety of factors including type, age, weight, sex; the route of administration; the renal and hepatic function of the patient; and the particular compound or salt thereof employed.
  • An ordinarily skilled physician or veterinarian can readily determine and prescribe the effective amount of the drug required to treat, for example, to prevent, inhibit (fully or partially) or arrest the progress of the disease.
  • compounds of the instant invention can be administered in a total daily dose of up to 10,000 mg.
  • Compounds of the instant invention can be administered once daily (QD), or divided into multiple daily doses such as twice daily (BID), and three times daily (TID).
  • Compounds of the instant invention can be administered at a total daily dosage of up to 10,000 mg, e.g., 2,000 mg, 3,000 mg, 4,000 mg, 6,000 mg, 8,000 mg or 10,000 mg, which can be administered in one daily dose or can be divided into multiple daily doses as described above.
  • compounds of the instant invention can be administered in a total daily dose of up to 1 ,000 mg.
  • Compounds of the instant invention can be administered once daily (QD), or divided into multiple daily doses such as twice daily (BID), and three times daily (TID).
  • Compounds of the instant invention can be administered at a total daily dosage of up to 1 ,000 mg, e.g., 200 mg, 300 mg, 400 mg, 600 mg, 800 mg or 1 ,000 mg, which can be administered in one daily dose or can be divided into multiple daily doses as described above.
  • intermittent administration of a compound of the instant invention may be administration one to six days per week or it may mean administration in cycles (e.g. daily administration for two to eight consecutive weeks, then a rest period with no administration for up to one week) or it may mean administration on alternate days.
  • the compounds of the instant invention may be administered according to any of the schedules described above, consecutively for a few weeks, followed by a rest period.
  • the compounds of the instant invention may be administered according to any one of the schedules described above from two to eight weeks, followed by a rest period of one week, or twice daily at a dose of 100 - 500 mg for three to five days a week.
  • the compounds of the instant invention may be administered three times daily for two consecutive weeks, followed by one week of rest.
  • any one or more of the specific dosages and dosage schedules of the compounds of the instant invention may also be applicable to any one or more of the therapeutic agents to be used in the combination treatment (hereinafter refered to as the "second therapeutic agent").
  • the specific dosage and dosage schedule of this second therapeutic agent can further vary, and the optimal dose, dosing schedule and route of administration will be determined based upon the specific second therapeutic agent that is being used.
  • the route of administration of the compounds of the instant invention is independent of the route of administration of the second therapeutic agent.
  • the administration for a compound of the instant invention is oral administration.
  • the administration for a compound of the instant invention is intravenous administration.
  • a compound of the instant invention is administered orally or intravenously, and the second therapeutic agent can be administered orally, parenterally, intraperitoneally, intravenously, intraarterially, trans dermally, sublingually, intramuscularly, rectally, transbuccally, intranasally, liposomally, via inhalation, vaginally, intraoccularly, via local delivery by catheter or stent, subcutaneously, intraadiposally, intraarticularly, intrathecally, or in a slow release dosage form.
  • a compound of the instant invention and second therapeutic agent may be administered by the same mode of administration, i.e. both agents administered e.g. orally, by IV.
  • a compound of the instant invention by one mode of administration, e.g. oral, and to administer the second therapeutic agent by another mode of administration, e.g. IV or any other ones of the administration modes described hereinabove.
  • the first treatment procedure, administration of a compound of the instant invention can take place prior to the second treatment procedure, i.e., the second therapeutic agent, after the treatment with the second therapeutic agent, at the same time as the treatment with the second therapeutic agent, or a combination thereof.
  • a total treatment period can be decided for a compound of the instant invention.
  • the second therapeutic agent can be administered prior to onset of treatment with a compound of the instant invention or following treatment with a compound of the instant invention.
  • the instant compounds are also useful in combination with other therapeutic agents. Combinations of the presently disclosed compounds with therapeutic agents are within the scope of the invention. A person of ordinary skill in the art would be able to discern which combinations of agents would be useful based on the particular characteristics of the drugs and the pathologies involved.
  • the instant compounds are also useful in combination with known therapeutic agents.
  • the instant compounds are useful in combination with a known antiinflammatory agent.
  • the anti-inflammatory agent is a nonsteroidal antiinflammatory drug (NSAID).
  • the NSAID is selected from the group consisting of salicylates, indomethacin, flurbiprofen, diclofenac, ketorolac, naproxen, piroxicam, tebufelone, ibuprofen, etodolac, nabumetone, tenidap, alcofenac, antipyrine, aminopyrine, dipyrone, aminopyrone, phenylbutazone, clofezone, oxyphenbutazone, prenazone, apazone, benzydamine, bucolome, cinchophen, clonixin, ditrazol, epirizole, fenoprofen, floctafenin, flufenamic acid, glaphenine, indoprofen, ketoprofen, loxoprofen, meclofenamic acid, mefenamic acid, niflumic acid, phenacetin, salidifamide
  • the NSAID is a selective COX-2 inhibitor.
  • NSAID's which are selective inhibitors of COX-2 are defined as those which possess a specificity for inhibiting COX-2 over COX-1 of at least 100 fold as measured by the ratio of IC50 for COX-2 over IC50 for COX-1 evaluated by cell or microsomal assays.
  • Such compounds include, but are not limited to those disclosed in U.S. Pat. 5,474,995, U.S. Pat. 5,861,419, U.S. Pat. 6,001,843, U.S. Pat. 6,020,343, U.S. Pat. 5,409,944, U.S. Pat. 5,436,265, U.S. Pat. 5,536,752, U.S. Pat. 5,550,142, U.S. Pat. 5,604,260, U.S. 5,698,584, U.S. Pat.
  • cancer to be the name for diseases in which the body's cells become abnormal and divide without control.
  • Cancers that may be treated by the compounds, compositions and methods of the invention include, but are not limited to: Cardiac: sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma and teratoma; Lung: bronchogenic carcinoma (squamous cell, undifferentiated small cell, undifferentiated large cell, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatous hamartoma, mesothelioma; Gastrointestinal: esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas
  • Genitourinary tract kidney (adenocarcinoma, Wilm's tumor [nephroblastoma], lymphoma, leukemia), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), testis (seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroma, fibroadenoma, adenomatoid tumors, lipoma); Liver: hepatoma (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma; Bone: osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytom
  • cystadenocarcinoma mucinous cystadenocarcinoma, unclassified carcinoma] granulosa-thecal cell tumors, Sertoli-Leydig cell tumors, dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonal
  • rhabdomyosarcoma fallopian tubes (carcinoma), breast; Hematologic: blood (myeloid leukemia [acute and chronic], acute lymphoblastic leukemia, chronic lymphocytic leukemia,
  • myeloproliferative diseases multiple myeloma, myelodysplastic syndrome
  • Hodgkin's disease non-Hodgkin's lymphoma [malignant lymphoma]
  • Skin malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Karposi's sarcoma, moles dysplastic nevi, lipoma, angioma, dermatofibroma, keloids, psoriasis
  • Adrenal glands neuroblastoma.
  • the term "cancerous cell” as provided herein includes a cell afflicted by any one of the above-identified conditions.
  • cancers that may be treated by the compounds, compositions and methods of the invention include, but are not limited to: lung cancer, pancreatic cancer, colon cancer, colorectal cancer, myeloid leukemias, acute myelogenous leukemia, chronic myelogenous leukemia, chronic myelomonocytic leukemia, thyroid cancer, myelodysplastic syndrome, bladder carcinoma, epidermal carcinoma, melanoma, breast cancer, prostate cancer, head and neck cancers, ovarian cancer, brain cancers, cancers of mesenchymal origin, sarcomas, tetracarcinomas, neuroblastomas, kidney carcinomas, hepatomas, non-Hodgkin's lymphoma, multiple myeloma, and anaplastic thyroid carcinoma.
  • cancers that may be treated by the compounds, compositions and methods of the invention include, but are not limited to: breast, prostate, colon, colorectal, lung, brain, testicular, stomach, pancrease, skin, small intestine, large intestine, throat, head and neck, oral, bone, liver, bladder, kidney, thyroid and blood.
  • AML acute myeloid leukemia
  • liposarcoma liposarcoma
  • colorectal cancer colorectal cancer
  • gastric cancer gastric cancer and melanoma.
  • ALL acute lymphoblastic leukemia
  • lymphoma lymphoma
  • lung breast and glioblastoma.
  • the compounds of the invention are also useful in preparing a medicament that may be useful in treating cancer.
  • the compounds of the invention are for the potential treatment of cancer.
  • the compounds of the invention may be useful to the treatment of a variety of cancers, including, but not limited to: carcinoma, including, but not limited to, of the bladder, breast, colon, rectum, endometrium, kidney, liver, lung, head and neck, esophagus, gall bladder, cervix, pancreas, prostrate, larynx, ovaries, stomach, uterus, sarcoma and thyroid cancer;
  • carcinoma including, but not limited to, of the bladder, breast, colon, rectum, endometrium, kidney, liver, lung, head and neck, esophagus, gall bladder, cervix, pancreas, prostrate, larynx, ovaries, stomach, uterus, sarcoma and thyroid cancer
  • hematopoietic tumors of the lymphoid lineage including leukemia, acute lymphocytic leukemia, chronic lymphocytic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell lymphoma, Hodgkins lymphoma, non-Hodgkins lymphoma, hairy cell lymphoma, mantle cell lymphoma, myeloma, and Burkett's lymphoma; hematopoetic tumors of myeloid lineage, including acute and chronic myelogenous leukemias, myelodysplastic syndrome and
  • tumors of the central and peripheral nervous system including astrocytoma, neuroblastoma, glioma, and schwannomas; and other tumors, including melanoma, skin (non- melanomal) cancer, mesothelioma (cells), seminoma, teratocarcinoma, osteosarcoma, xenoderoma pigmentosum, keratoctanthoma, thyroid follicular cancer and Kaposi's sarcoma.
  • the compounds of the invention may be useful for the treatment of activated B- cell-like diffuse large B-cell lymphoma (ABC-DLBCL), chronic lymphocytic leukemia (CLL) and Waldenstrom's Macroglobulinemia.
  • ABSC-DLBCL activated B- cell-like diffuse large B-cell lymphoma
  • CLL chronic lymphocytic leukemia
  • the instant compounds are useful in combination with a known anti-cancer agent.
  • Combinations of the presently disclosed compounds with anti-cancer agents are within the scope of the invention.
  • Examples of such anti-cancer agents can be found in Cancer Principles and Practice of Oncology by V.T. Devita and S. Hellman (editors), 6th edition (February 15, 2001), Lippincott Williams & Wilkins Publishers.
  • a person of ordinary skill in the art would be able to discern which combinations of agents would be useful based on the particular characteristics of the drugs and the cancer involved.
  • Such agents include the following: estrogen receptor modulators, androgen receptor modulators, retinoid receptor modulators, cytotoxic/cytostatic agents, antiproliferative agents, prenyl-protein transferase inhibitors, HMG-CoA reductase inhibitors and other angiogenesis inhibitors, HIV protease inhibitors, reverse transcriptase inhibitors, inhibitors of cell proliferation and survival signaling, bisphosphonates, aromatase inhibitors, siRNA therapeutics, ⁇ -secretase inhibitors, agents that interfere with receptor tyrosine kinases (RTKs) and agents that interfere with cell cycle checkpoints.
  • RTKs receptor tyrosine kinases
  • the anti-cancer agent is selected from the group consisting of abarelix (Plenaxis depot®); aldesleukin (Prokine®); Aldesleukin (Proleukin®); Alemtuzumabb (Campath®); alitretinoin (Panretin®); allopurinol (Zyloprim®); altretamine (Hexalen®);
  • amifostine (Ethyol®); anastrozole (Arimidex®); arsenic trioxide (Trisenox®); asparaginase (Elspar®); azacitidine (Vidaza®); bevacuzimab (Avastin®); bexarotene capsules (Targretin®); bexarotene gel (Targretin®); bleomycin (Blenoxane®); bortezomib (Velcade®); busulfan intravenous (Busulfex®); busulfan oral (Myleran®); calusterone (Methosarb®); capecitabine (Xeloda®); carboplatin (Paraplatin®); carmustine (BCNU®, BiCNU®); carmustine (Gliadel®); carmustine with Polifeprosan 20 Implant (Gliadel Wafer®); celecoxib (Celebrex®); cetuximab (Erbitux®); chloramb
  • daunorubicin daunomycin
  • daunorubicin daunomycin
  • daunomycin daunomycin (Cerubidine®)
  • Denileukin diftitox Ontak®; dexrazoxane (Zinecard®); docetaxel (Taxotere®); doxorubicin (Adriamycin PFS®); doxorubicin (Adriamycin®, Rubex®); doxorubicin (Adriamycin PFS Injection®); doxorubicin liposomal (Doxil®); dromostanolone propionate (dromostanolone®); dromostanolone propionate (masterone injection®); Elliott's B Solution (Elliott's B Solution®); epirubicin (Ellence®); Epoetin alfa (epogen®); erlotinib (Tarceva®); estramustine (Emcyt®); etoposide phosphate (Etopophos®); etoposide, VP-16 (Vepesid®); exemestan
  • lomustine, CCNU (CeeBU®); meclorethamine, nitrogen mustard (Mustargen®); megestrol acetate (Megace®); melphalan, L-PAM (Alkeran®); mercaptopurine, 6-MP (Purinethol®); mesna (Mesnex®); mesna (Mesnex tabs®); methotrexate (Methotrexate®); methoxsalen
  • Rituximab (Rituxan®); sargramostim (Leukine®); Sargramostim (Prokine®); sorafenib
  • Teslac® thioguanine, 6-TG (Thioguanine®); thiotepa (Thioplex®); topotecan (Hycamtin®); toremifene (Fareston®); Tositumomab (Bexxar®); Tositumomab/I-131 tositumomab (Bexxar®); Trastuzumab (Herceptin®); tretinoin, ATRA (Vesanoid®); Uracil Mustard (Uracil Mustard Capsules®); valrubicin (Valstar®); vinblastine (Velban®); vincristine (Oncovin®); vinorelbine (Navelbine®); zoledronate (Zometa®) and vorinostat (Zolinza®); a pharmaceutically acceptable salt thereof, and a mixture thereof.
  • ATRA Vesanoid®
  • Uracil Mustard Uracil Mustard Capsule
  • administration means introducing the compound or a prodrug of the compound into the system of the animal in need of treatment.
  • a compound of the invention or prodrug thereof is provided in combination with one or more other active agents (e.g., a cytotoxic agent, etc.)
  • administration and its variants are each understood to include concurrent and sequential introduction of the compound or prodrug thereof and other agents.
  • composition is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.
  • terapéuticaally effective amount means that amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue, system, animal or human that is being sought by a researcher, veterinarian, medical doctor or other clinician. Further included within the scope of the invention is a method for treating an inflammatory disease which comprises administering to a mammal in need thereof a
  • a method for treating an inflammatory disease which comprises administering to a mammal in need thereof a
  • inflammatory disease is selected from rheumatoid arthritis, inflammatory bowel disease and cancer.
  • the compounds of the instant invention are useful for the treatment and/or reducing the severity of rheumatoid arthritis.
  • the compounds of the instant invention are useful for the treatment and/or reducing the severity of inflammatory bowel disease.
  • the compounds of the instant invention are useful for the treatment and/or reducing the severity of lupus.
  • the compounds of the instant invention are useful for the treatment and/or reducing the severity of cancer.
  • the compounds of the instant invention are useful for the treatment of rheumatoid arthritis.
  • the compounds of the instant invention are useful for the treatment of inflammatory bowel disease.
  • the compounds of the instant invention are useful for the treatment of lupus.
  • the compounds of the instant invention are useful for the treatment of cancer.
  • a method of treating an inflammatory disease which comprises administering a therapeutically effective amount of a compound of the instant invention in combination with a second therapeutic agent.
  • a method of treating an inflammatory disease which comprises administering a therapeutically effective amount of a compound of the instant invention in combination with a second therapeutic agent, wherein the second therapeutic agent is selected from an anti-cancer agent and an anti-inflammatory agent.
  • Intermediate B is prepared via [2,3]-cycloaddition between dicyano[3- (methylsulfanyl)-l,2,4-triazin-l-ium-l-yl]methanide (A) and ethenesulfinylbenzene at an elevated temperature (Scheme 1).
  • Intermediate A is prepared from 3-(methylsulfanyl)-l,2,4- triazine by employing oxirane-2,2,3,3-tetracarbonitrile.
  • compounds of formula L are prepared from 7-Bromo-2- (methylthio)pyrrolo[2,l-
  • Intermediates N are prepared from H via oxidation with mCPBA and S N Ar reaction with an array of amines.
  • Intermediates N are converted to intermediates O via palladium-mediated carbonylation in methanol followed by hydrolysis of the resultant methyl ester.
  • Intermediates O are coupled with various aryl-amines employing coupling reagents such as HATU to afford compounds L.
  • Step 1 Into a 500 mL 3 necked round bottom flask purged and maintained with an inert atmosphere of nitrogen was placed a solution of 3-(methylsulfanyl)-l,2,4-triazine (24 g, 190 mmol) in THF (170 mL). This was followed by the addition of oxirane-2,2,3,3-tetracarbonitrile (30 g, 210 mmol) in portions. The resulting solution was stirred for 6 h at 45 °C and cooled to room temperature. The solid was collected by filtration and dried in an oven under reduced pressure. This resulted in dicyano[3-(methylsulfanyl)-l,2,4-triazin-l-ium-l-yl]methanide as a solid.
  • Step 2 Into a 1000 mL 3 necked round bottom flask purged and maintained with an inert atmosphere of nitrogen were placed a solution of dicyano[3-(methylsulfanyl)-l,2,4-triazin-l- ium-l-yl]methanide (44 g, 230 mmol) in dioxane (500 mL) and ethenesulfinylbenzene (45 g, 300 mmol).
  • Step 1 Into a 5 L round bottom flask containing a solution of lH-pyrrole-2-carboxylic acid methyl ester (15.0 g, 120 mmol) in tetrahydrofuran (500 mL) was added a solution of potassium fert-butoxide (35 g, 310 mmol) in tetrahydrofuran (500 mL) and the reaction mixture was stirred at room temperature for 30 min. A solution of monochloramine (0.15 M in diethyl ether, 2.1 L) was added at 10 °C over 20 min, while bubbling nitrogen into the reaction mixture and stirred at room temperature for 2 h.
  • Aqueous Na2S2C>3 (500 mL) was added dropwise at 10 °C over 30 min and the reaction was stirred for 1 h. The organic layer was separated, washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford methyl 1 -amino- lH-pyrrole-2-carboxylate.
  • Step 2 Into a 2 L round bottom flask containing a solution of methyl 1 -amino- lH-pyrrole-2- carboxylate (14 g, 97 mmol) in tetrahydrofuran (500 mL) was added benzoyl isothiocyanate (14 g, 85 mmol) in tetrahydrofuran (100 mL) dropwise at room temperature and the reaction was stirred overnight.
  • Step 3 A mixture of methyl l-(3-benzoylthioureido)-lH-pyrrole-2-carboxylate (8.0 g 26 mmol) and aqueous sodium hydroxide (2 M in water, 250 mL) in 500 mL round bottom flask was heated at 85 °C for 75 min. The reaction mixture was neutralized by addition of hydrochloric acid (6 N, 20 mL). The solvent was evaporated under reduced pressure and the residue was purified by flash chromatography eluting with methanol in dichloromethane (20-30%) to afford 2-mercaptopyrrolo[2,l-/] [l,2,4]triazin-4(3H)-one as a solid. MS calc'd [M-H] + 166.0, found 166.0.
  • Step 4 Into a 100 mL round bottom flask containing a solution of 2-mercaptopyrrolo[2,l-
  • Step 5 Into a 100 mL sealed tube were added 2-(methylthio)pyrrolo[2,l-/] [l,2,4]triazin-4(3H)- one (2.5 g, 13 mmol) and phosphorous oxy chloride (25 mL) followed by the addition of NN- diisopropylethylamine (2.3 mL, 1.76 mmol) and the reaction mixture was stirred at 110 °C overnight. The solvent was evaporated under reduced pressure and the residue was dissolved in dichloromethane (100 mL) and washed with water and brine solution.
  • Step 6 Into a 100 mL round bottom flask containing a solution of 4-chloro-2- (methylthio)pyrrolo[2,l-
  • Step 7 & 8 Into a 100 mL round bottom flask containing a solution of 7-bromo-4-chloro-2- (methylthio)pyrrolo[2,l-
  • Step 1 Into a 100 mL round bottom flask containing a solution of methyl l-methyl-4-nitro-lH- pyrazole-3-carboxylate (1.5 g, 8 mmol) in dichloromethane (30 mL) was added
  • Step 2 Into a 50 mL round bottom flask containing a solution of 2-iodoxybenzoic acid (2.8 g, 10 mmol) in dimethyl sulfoxide (3 mL) was added a solution of (l-methyl-4-nitro-lH-pyrazol- 3-yl)methanol (800 mg, 5 mmol) in dimethyl sulfoxide (3 mL) and the reaction mixture was stirred at room temperature for 3 h. The reaction mixture was diluted with diethyl ether and washed with water and brine. The organic fraction was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash
  • Step 3 Into a 25 mL round bottom flask containing a solution of l-methyl-4-nitro-lH-pyrazole- 3-carbaldehyde (300 mg, 1.9 mmol) in dichloromethane (5 mL) was added diethylaminosulfur trifluoride (0.76 mL, 5.8 mmol) at -20 °C and the reaction was stirred at room temperature for 16 h. The reaction mixture was concentrated under reduced pressure and the residue was purified by flash chromatography eluting with methanol in dichloromethane (3-5%) to yield 3- (difluoromethyl)-l-methyl-4-nitro-lH-pyrazole.
  • ⁇ ⁇ NMR (CDC1 3 , 400 MHz): 5 8.19 (s, 1H), 7.13 (t, J 53.2 Hz, 1H), 4.03 (s, 3H).
  • Step 4 Into a 25 mL round bottom flask containing a solution of 3-(difluoromethyl)-l-methyl-4- nitro-lH-pyrazole (300 mg, 1.93 mmol) in methanol (3 mL) was added palladium on carbon (15 mg, 5% w/w) and the reaction was stirred at room temperature for 8 h under hydrogen bladder pressure. The reaction mixture was filtered through celite and washed with methanol and the filtrate was concentrated under reduced pressure. The residue was purified by flash
  • Step 1 Into a 250 mL round bottom flask containing a suspension of 4-nitro-lH-pyrazole-3- carboxylic acid (20.0 g, 127 mmol) in methanol (100 mL) was added concentrated sulfuric acid (4 mL) drop wise over 5 min at 0 °C and the resulting slurry was refluxed at 80 °C for 16 h. The solvent was removed under reduced pressure and the residual mass was dissolved in ethyl acetate (300 mL) and washed with saturated aqueous sodium bicarbonate solution (2 x 100 mL) and brine (100 mL) and dried over anhydrous sodium sulfate.
  • Step 2 Into a 1 L round bottom flask containing a suspension of sodium hydride (60% in paraffin oil, 4.7 g, 116 mmol) in tetrahydrofuran (400 mL) at 0 °C was added methyl 4-nitro-lH- pyrazole-3-carboxylate (16.5 g, 96 mmol) in tetrahydrofuran (50 mL) dropwise and the reaction mixture was stirred for 1 h. To the reaction mixture was added methyl iodide (9 mL, 145 mmol) and the mixture was stirred at room temperature for 3 h.
  • Step 3 Into a 250 mL sealed tube were added methyl l-methyl-4-nitro-lH-pyrazole-3- carboxylate (2.5 g, 13.5 mmol) and methanol (60 mL) and the reaction mixture was cooled to -60 °C and ammonia gas was purged for 15 min and then heated at 80 °C for 4 h. The reaction mixture was cooled to -15 °C and the excess ammonia gas was carefully removed by bubbling nitrogen and concentrated under reduced pressure to afford l-methyl-4-nitro-lH-pyrazole-3- carboxamide as a solid.
  • Step 4 Into a 250 mL sealed tube containing a solution of l-methyl-4-nitro-lH-pyrazole-3- carboxamide (2.0 g, 12 mmol) in dichloromethane (100 mL) was added NN- diisopropylethylamine (13 mL, 71 mmol) at 0 °C. To this reaction mixture was added phosphorous oxy chloride (3.3 mL, 35 mmol) dropwise and the mixture was stirred at room temperature for 1 h. The reaction was treated with saturated sodium bicarbonate solution and extracted with dichloromethane. The combined organics were washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure.
  • Step 5 Into a 250 mL round bottom flask containing a solution of l-methyl-4-nitro-lH- pyrazole-3-carbonitrile (3.5 g, 23 mmol) in methanol (100 mL) at room temperature was added palladium on carbon (0.5 g, 15% w/w) and the reaction mixture was stirred at room temperature under hydrogen bladder atmosphere for 2 h. The reaction mixture was filtered through celite and washed with methanol and dichloromethane. The filtrate was concentrated under reduced pressure to afford 4-amino-l -methyl- lH-pyrazole-3-carbonitrile as a solid.
  • X H NMR (CD 3 OD, 400 MHz): ⁇ 7.22 (s, 1H), 3.84 (s, 3H). MS calc'd [M+H] + 123.1, found 123.4.
  • Step 1 Into a 250 mL round bottom flask containing a solution of 3 -amino- 1 -methyl- 1H- pyrazole (5.0 g, 52 mmol) in dichloromethane (100 mL) at 0 °C was added triethylamine (18 mL, 129 mmol). After 10 min, trifluoroacetic anhydride (9.5 mL, 67 mmol) was added and the reaction mixture was stirred at room temperature for 2 h.
  • Step 2 Into a 100 mL round bottom flask containing a solution of 2,2,2-trifluoro-N-(l-methyl- lH-pyrazol-3-yl)acetamide (8.5 g, 44 mmol) in concentrated sulfuric acid (14 mL) was added fuming nitric acid (14 mL) at 0 °C dropwise and the reaction was stirred at room temperature for 2 h. The reaction mixture was treated with ice cold water and extracted with ethyl acetate.
  • Step 3 Into a 500 mL round bottom flask containing a solution of 2,2,2-trifluoro-N-(l-methyl-4- nitro-lH-pyrazol-3-yl)acetamide (8.5 g, 36 mmol) in methanol (200 mL) and water (50 mL) was added potassium carbonate (12.5 g, 89 mmol) and the reaction was stirred at room temperature for 24 h. The mixture was concentrated under reduced pressure and the residue was dissolved in ethyl acetate (150 mL), washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure.
  • Step 4 Into a 250 mL round bottom flask containing a solution of copper(II) bromide (3.0 g, 14 mmol) and fert-butyl nitrite (1.7 mL, 14 mmol) in acetonitrile (150 mL) was added l-methyl-4- nitro-lH-pyrazol-3-amine (2 g, 14 mmol) in acetonitrile (20 mL) at 0 °C and the reaction was stirred at room temperature for 2 h. The reaction mixture was concentrated under reduced pressure.
  • Step 5 Into a 100 mL round bottom flask containing a solution of 3-bromo-l-methyl-4-nitro- lH-pyrazole (1.0 g) in ethyl acetate (50 mL) at room temperature was added Raney Nickel (700 mg) and the reaction mixture was stirred at room temperature for 16 h under hydrogen atmosphere. The reaction mixture was filtered through celite and washed with ethyl acetate. The filtrate was concentrated under reduced pressure and purified by flash chromatography eluting with ethyl acetate in petroleum ether (40-50%) to afford 3-bromo-l -methyl- lH-pyrazol- 4-amine as a liquid. l NMR (CD 3 OD, 400 MHz): ⁇ 7.18 (s, 1H), 3.77 (s, 3H). MS calc'd [M+H] + 176.0, found 176.2.
  • Step 1 Into a 250 mL round bottom flask containing a solution of l-methyl-4-nitro-lH-pyrazol- 3-amine (4.0 g, 28 mmol) in acetonitrile (100 mL) was added concentrated hydrochloric acid (8 mL) dropwise at 0 °C. To this reaction mixture was added sodium nitrite (8.0 g, 116 mmol) in portions and the reaction mixture was gradually brought to room temperature and stirred for 16 h. The reaction mixture was cooled to 0 °C, treated with water (30 mL) and extracted with ethyl acetate (2x50 mL).
  • Step 2 Into a 100 mL round bottom flask containing a solution of 3-chloro-l-methyl-4-nitro- lH-pyrazole (2.0 g) in ethyl acetate (50 mL) was added Raney Ni (1.0 g) and the reaction mixture was stirred under hydrogen atmosphere for 24 h. The reaction mixture was filtered through celite and washed with ethyl acetate. The filtrate was concentrated under reduced pressure and purified by flash chromatography eluting with ethyl acetate in petroleum ether (40- 50%) to afford 3 -chloro-1 -methyl- lH-pyrazol-4-amine as an oil.
  • Step 1 Into a 100 mL round bottom flask containing a solution of thiophene-3-carboxylic acid (4.0 g, 31 mmol) in toluene (40 mL) were added diphenylphosphoryl azide (9.5 g, 34 mmol) and NN-diisopropylethylamine (6.7 mL, 38 mmol) at 0 °C and the reaction was stirred at room temperature for 1 h. The reaction mixture was cooled to 0 °C, treated with fert-butanol (12 mL, 124 mmol) and heated to 120 °C for 5 h.
  • diphenylphosphoryl azide 9.5 g, 34 mmol
  • NN-diisopropylethylamine 6.7 mL, 38 mmol
  • Step 2 Into a 100 mL round bottom flask containing a solution of fert-butyl thiophen-3- ylcarbamate (4.2 g, 21 mmol) in carbon tetrachloride (40 mL) was added N-bromosuccinimide (7.5 g, 42 mmol) and the reaction mixture was heated at 80 °C for 2 h. The reaction mixture was diluted with ethyl acetate (100 mL), washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure.
  • N-bromosuccinimide 7.5 g, 42 mmol
  • Step 3 Into a 10 mL round bottom flask containing a solution of fert-butyl (2-bromothiophen-3- yl)carbamate (500 mg) in dichloromethane (5 mL) was added HBr in acetic acid (0.5 mL) dropwise at 0 °C and reaction mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated under reduced pressure and triturated using diethyl ether to afford 2- bromothiophen-3-amine hydrobromide as a solid.
  • Step 2 Into a 25 mL round bottom flask tert-butyl (2-(trifluoromethyl)thiophen-3-yl)carbamate (800 mg) in dichloromethane (10 mL) was added HBr in acetic acid (1 mL) at 0 °C and the mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated under reduced pressure and triturated using diethyl ether to afford 2-(trifluoromethyl)thiophen-3-amine hydrobromide as a solid.
  • Step 1 Into a 100 mL round bottom flask containing a solution of 3,4-dibromothiophene (5.0 g, 21 mmol) in toluene (50 mL) were added benzophenone imine (4.1 g, 23 mmol), palladium acetate (140 mg, 0.6 mmol), 2,2'-bis(diphenylphosphino)-l , l'-binaphthyl (510 mg, 0.83 mmol) and cesium carbonate (13.4 g, 41 mmol) and the reaction mixture was degassed for 15 min using nitrogen gas and heated at 1 10 °C for 16 h.
  • benzophenone imine 4.1 g, 23 mmol
  • palladium acetate 140 mg, 0.6 mmol
  • 2,2'-bis(diphenylphosphino)-l l'-binaphthyl
  • cesium carbonate (13.4 g, 41 mmol
  • Step 2 Into a 50 mL round bottom flask containing a solution of N-(4-bromothiophen-3-yl)-l,l- diphenylmethanimine (4.0 g, 12 mmol) in dichloromethane (20 mL) was added hydrochloric acid (4 M solution in 1,4-dioxane, 10 mL) at 0 °C and the reaction was stirred at room temperature for 4 h. The reaction mixture was concentrated under reduced pressure, triturated using diethyl ether and dried under high vacuum to afford 4-bromothiophen-3 -amine
  • Step 1 Into a 250 mL round bottom flask containing a solution of methyl 4-aminothiophene-3- carboxylate (2.5 g, 16 mmol) in concentrated hydrochloric acid (21 mL) was added sodium nitrite (1.2 g, 18 mmol) in water (5 mL) dropwise at 0 °C and the reaction mixture was stirred at for 1 h. The mixture was treated with copper(I) chloride (2.5 g, 19 mmol) in chloroform (25 mL) and heated at 50 °C for 16 h. The reaction mixture was cooled to room temperature, treated with saturated sodium carbonate solution and extracted with dichloromethane (3 x 50 mL).
  • Step 2 Into a 25 mL round bottom flask containing a solution of methyl 4-chlorothiophene-3- carboxylate (600 mg, 3.4 mmol) in tetrahydrofuran (6 mL) and water(l mL) was added lithium hydroxide monohydrate (240 mg, 10 mmol) and the reaction was stirred at room temperature for 16 h . The mixture was concentrated under reduced pressure and acidified to pH 2 using diluted hydrochloric acid (1.5 N). The reaction mixture was extracted with ethyl acetate.
  • Step 3 Into a 100 mL round bottom flask containing a solution of 4-chlorothiophene-3- carboxylic acid (500 mg, 3 mmol) in toluene (20 mL) were added diphenylphosphoryl azide (2.5 g, 3.4 mmol) and NN-diisopropylethylamine (0.7 mL, 3.7 mmol) and the reaction was stirred at room temperature for 1 h. To this mixture was added fert-butanol (1.2 mL, 12 mmol) and the mixture was heated at 100 °C for 3 h.
  • diphenylphosphoryl azide 2.5 g, 3.4 mmol
  • NN-diisopropylethylamine 0.7 mL, 3.7 mmol
  • Step 4 Into a 10 mL round bottom flask containing a solution of fert-butyl (4-chlorothiophen-3- yl)carbamate (400 mg, 1.7 mmol) in dichloromethane (4 mL) was added hydrochloric acid solution (4M solution in 1,4-dioxane, 0.3 mL) and the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated under reduced pressure, triturated with diethyl ether and dried under high vacuum to afford 4-chlorothiophen-3 -amine
  • Step 1 Into a 100 mL round bottom flask containing a solution of 3,4-dibromothiophene (4.0 g, 17 mmol) in diethyl ether (50 mL) was added w-butyl lithium in hexane (1 M solution in hexanes, 17 mL, 17 mmol) at -78 °C over 15 min. To this mixture was added NN- dimethylformamide and the reaction was stirred for 3 h. The reaction mixture was treated with saturated ammonium chloride solution and extracted with diethyl ether (2 x 50 mL).
  • Step 2 Into a 50 mL round bottom flask containing a solution of 4-bromothiophene-3- carbaldehyde (3.5 g, 18 mmol) in dichloromethane (40 mL) was added diethylaminosulfur trifluoride (7.3 mL, 55 mmol) at 0 °C and the reaction was stirred at room temperature for 16 h. The reaction mixture was diluted with dichloromethane (20 mL) and washed with saturated sodium bicarbonate solution, water and brine. The solution was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and purified by flash column
  • Step 3 A solution of 3-bromo-4-(difluoromethyl)thiophene (800 mg, 4 mmol) in NN- dimethylformamide (10 mL) at 0 °C was purged with ammonia gas for 1 h. To this mixture were added potassium phosphate tribasic (2.4 g, 11 mmol) and copper(II) acetylacetonate (300 mg, 1.9 mmol) and the reaction mixture was heated at 90 °C for 16 h.
  • Step 1 Into a 250 mL round bottom flask containing a solution of methyl 2-formylbenzoate (5.0 g, 30 mmol) in dichloromethane (80 mL) were added diethylaminosulfur trifluoride (7 mL, 52 mmol) and methanol (1.5 mL) at -5 °C and the reaction was stirred at room temperature for 16 h. The reaction mixture was diluted with dichloromethane (20 mL) and washed with saturated sodium bicarbonate solution, water and brine.
  • Step 2 Into a 100 mL round bottom flask containing a solution of methyl 2- (difluoromethyl)benzoate (4.3 g, 23 mmol) in tetrahydrofuran (30 mL) and water (15 mL) was added lithium hydroxide monohydrate (2.9 g, 69 mmol) at 0 °C and the reaction mixture was stirred at room temperature for 16 h. The reaction mixture was concentrated under reduced pressure and acidified to pH 2 using diluted hydrochloric acid (1.5 N).
  • Step 3 Into a 100 mL round bottom flask containing a solution of 2-(difluoromethyl)benzoic acid (4.0 g, 23 mmol) in toluene (50 mL) were added diphenylphosphoryl azide (5.5 mL, 26 mmol), NN-diisopropylethylamine (5 mL, 28 mmol) and fert-butanol (7 mL) and the mixture was stirred at room temperature for 30 min and at 110 °C for 16 h. The reaction mixture was concentrated under reduced pressure.
  • diphenylphosphoryl azide 5.5 mL, 26 mmol
  • NN-diisopropylethylamine 5 mL, 28 mmol
  • fert-butanol 7 mL
  • Step 4 Into a 10 mL round bottom flask containing a solution of fert-butyl (2-
  • Step 1 Into a 500 mL round bottom flask containing a solution of cyclohexa-l,4-diene (5.0 g, 63 mmol) in acetonitrile (150 mL) were added N-methyl morpholine N-oxide (7.0 g, 63 mmol) and osmium tetroxide (4% wt in H 2 0, 0.2 mL) at 0 °C and the reaction was stirred at room temperature for 5 h. The reaction mixture was diluted with ethyl acetate and washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure.
  • N-methyl morpholine N-oxide 7.0 g, 63 mmol
  • osmium tetroxide 4% wt in H 2 0, 0.2 mL
  • Step 2 Into a 250 mL round bottom flask containing a solution of cyclohex-4-ene-l,2-diol (2.8 g, 25 mmol) in dichloromethane (50 mL) were added triethylamine (10.0 mL, 74 mmol) and methanesulfonic anhydride (8.5 g, 50 mmol) and the reaction mixture was stirred at room temperature for 1 h. The reaction mixture was diluted with dichloromethane and washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure.
  • Step 3 Into a 250 mL round bottom flask containing a solution of cyclohex-4-ene-l,2-diyl dimethanesulfonate (3.8 g, 14 mmol) in dimethyl sulfoxide (40 mL) was added sodium azide (2.7 g, 43 mmol) and the reaction mixture was stirred at 80 °C for 48 h. The reaction mixture was cooled to room temperature, diluted with ethyl acetate, washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure.
  • Steps 4 & 5 Into a 250 mL round bottom flask containing a solution of 4,5-diazidocyclohex-l- ene (1.3 g, 8 mmol) in tetrahydrofuran (30 mL) was added lithium aluminum hydride (1M THF, 16 mL, 16 mmol) dropwise at 0 °C and the reaction mixture was stirred at room temperature for 1 h. The reaction mixture was treated with saturated sodium sulfate and the precipitate was filtered through celite and washed with ethyl acetate. The filtrate was concentrated under reduced pressure and crude product obtained was taken to the next step without further purification.
  • lithium aluminum hydride (1M THF, 16 mL, 16 mmol
  • Step 6 Into a 100 mL round bottom flask containing a solution of dibenzyl cyclohex-4-ene-l,2- diyldicarbamate (1.7 g, 4.4 mmol) in tetrahydrofuran (35 mL) was added borane-methyl sulfide complexe (1.2 mL) at 0 °C and the reaction was stirred at room temperature for 14 h. To this reaction mixture were added sodium hydroxide (10% in water, 14 mL) and hydrogen peroxide (30%, 14 mL) and the reaction was stirred for 1 h at room temperature.
  • Step 7 Into a 250 mL round bottom flask containing a solution of dibenzyl (4- hydroxycyclohexane-1, 2-diyl) dicarbamate (1.5 g, 3.7 mmol) in dichloromethane (60 mL) was added Dess-Martin periodinane (4.7 g, 11 mmol) at 0 °C, and reaction was strirred at room temperature overnight. The reaction mixture was treated with saturated sodium bicarbonate solution, washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure.
  • Step 8 Into a 50 mL round bottom flask containing a solution of dibenzyl (4-oxocyclohexane-l, 2-diyl) dicarbamate (1.0 g, 2.5 mmol) in dichloromethane (30 mL) was added diethylaminosulfur trifluoride (0.7 mL, 5 mmol) at 0 °C and the reaction was stirred at room temperature for 16 h. The reaction mixture was treated with saturated sodium bicarbonate solution, washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure.
  • Step 9 A mixture of dibenzyl (( ⁇ S,2R)- or (li?,25 -4,4-difluorocyclohexane-l,2- diyl)dicarbamate (Isomer 1) (1.4 g, 3.4 mmol) and hydrobromic acid solution (33% in acetic acid, 15 mL) was taken in a 50 mL round bottom flask and the reaction mixture was stirred at room temperature for 1 h. The solvent was removed under reduced pressure to afford ( ⁇ S,2R)- or (li?,25 -4,4-difluorocyclohexane-l,2-diamine hydrobromide.
  • Step 1 & 2 Into a 2 L round bottom flask containing a solution of frara-4-hydroxy-L-proline (25.0 g, 191 mmol) in methanol (1.2 L) at 0 °C was added thionyl chloride (17 mL, 229 mmol) dropwise and the reaction mixture was heated at reflux for 16 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure to afford methyl (2S,4R)-4- hydroxypyrrolidine-2-carboxylate (30 g) which was taken to the next step without further purification.
  • Step 3 & 4 Into a 1 L round bottom flask containing a solution of (2S,4i ⁇ !-methyl 4-hydroxy-l- [(4-methoxyphenyl)methyl]pyrrolidine-2-carboxylate (20.0 g, 75 mmol) in dichloromethane (130 mL) at 0°C were added triethylamine (45 mL, 325 mmol) and methanesulfonyl chloride (13.0 mL, 162 mmol) and the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with dichloromethane (200 mL) and washed with saturated sodium bicarbonate solution (300 mL), water and brine.
  • dichloromethane 200 mL
  • saturated sodium bicarbonate solution 300 mL
  • Step 5 & 6 Into a 1 L round bottom flask containing a suspension of lithium aluminum hydride (8.0 g, 210 mmol) in tetrahydrofuran (500 mL) at 0 °C was added a solution of methyl (2S,4R)- 4-azido-l-[(4-methoxyphenyl)methyl]pyrrolidine-2-carboxylate (16 g, 55 mmol) in
  • the crude product was dissolved in dioxane (600 mL) and di-fer /-butyl dicarbonate (25.0 g, 220 mmol) was added and the reaction mixture was stirred at room temperature for 12 h.
  • the mixture was diluted with ethyl acetate (200 mL) and washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure.
  • Step 7 Into a 500 mL round bottom flask containing a solution of fert-butyl N-[(3R,5S)-5- (hydroxymethyl)-l-[(4-methoxyphenyl)methyl]pyrrolidin-3-yl]carbamate (12.0 g, 34 mmol) in tetrahydrofuran (250 mL) was added diethylaminosulfur trifluoride (6.0 mL, 48 mmol) at 0 °C and the reaction was stirred at 0 °C for 1 h and at room temperature for 12 h. The reaction mixture was cooled to 0 °C and treated with saturated sodium bicarbonate solution (30 mL).
  • reaction mixture was extracted with ethyl acetate (2 x 100 mL) and combined organic fractions were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography eluting with ethyl acetate in petroleum ether (10-12%) to afford tert-butyl ((35',5i?)-5-fluoro-l -(4-methoxybenzyl)piperidin-3- yl)carbamate as a solid.
  • Step 1 Into a 5 L 4 necked round bottomed flask was placed a solution of diethyl malonate (300 g, 1.87 mol) and 1,2-dibromoethane (634.5 g, 3.38 mol) in DMSO (1.5 L). The mixture was treated with K 2 C0 3 (1020 g, 7.39 mol) and Bu 4 NHS0 4 (6.4 g, 19 mmol). The resulting solution was allowed to stir for 48 h at room temperature. The reaction mixture was treated with 2 L of H 2 0 and extracted with 1.5 L of EtOAc (3x). The organic layers were combined, dried over Na 2 S04 and concentrated under reduced pressure. The residue was distilled under 5-10 mmHg vacuum at 64-65 °C. This resulted in 400 g (90%) of diethyl cyclopropane-l,l-dicarboxylate as an oil.
  • Step 2 Into a 100 mL 3 necked round bottomed flask was placed THF (50 mL), then added LiAlH 4 (2 g, 53 mmol) in several batches. This was followed by the addition of a solution of diethyl cyclopropane- 1,1-dicarboxylate (5 g, 27 mmol) in THF (10 mL) dropwise with stirring, while cooling to 0 °C. The resulting solution was allowed to stir for 1 h at 0-5 °C in an ice bath. The reaction mixture was then treated with 2 mL of H 2 0, 6 mL of 15% NaOH solution and 2 mL of H 2 0. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was extracted with 50 mL of EtOAc. The organic layer was dried over Na 2 SC>4 and concentrated under reduced pressure to afford 2.7 g of cyclopropane-l,l-diyldimethanol as a liquid.
  • Step 3 Into a 2 L 3 necked round bottomed flask were placed a solution of cyclopropane- 1,1- diyldimethanol (42 g, 410 mmol) in DCM (200 mL) and DMAP (126 g, 1.03 mol). The mixture was treated with a solution of TsCl (173 g, 907 mmol) in DCM (500 mL) dropwise, while cooling to 0 °C, over 30 min. The resulting solution was allowed to stir for 2.5 h at room temperature. The reaction mixture was washed with H 2 0, HC1 (IN) and brine, dried over Na 2 SC>4 and concentrated under reduced pressure. This resulted in cyclopropane- 1,1- diyldimethanediyl bis(4-methylbenzenesulfonate) as a solid
  • Step 4 Into a 5 L 4 necked round bottomed flask was placed a solution of 4-methylbenzene-l- sulfonyl chloride (487 g, 2.55 mol) in ethyl ether (1 L). To the mixture was added a solution of ethane- 1,2-diamine (77 g, 1.3 mol) and sodium hydroxide (102 g, 2.55 mol) in H 2 0 (1 L) dropwise while cooled to 0 °C. The resulting solution was allowed to stir for 30 min at 0 °C in an ice bath, then overnight at room temperature. A filtration was performed and the filter cake was washed 2 times with H 2 0 and dried in an oven. This resulted in (crude) N,N-ethane-l,2- diylbis(4-methylbenzenesulfonamide) as a solid.
  • N,N-ethane-l,2-diylbis(4- methylbenzenesulfonamide) 150 g, 408 mmol
  • cyclopropane- 1,1-diyldimethanediyl bis(4- methylbenzenesulfonate) 200 g, 487 mmol
  • 18-crown-6 53 g, 200 mmol
  • THF 2 L
  • t-BuOK 100 g, 893 mmol
  • THF 500 mL
  • Step 5 Into a 5 L 4 necked round bottomed flask was placed a solution of 5,8-bis[(4- methylphenyl)sulfonyl]-5,8-diazaspiro[2.6]nonane (100 g, 230 mmol) in MeOH (1500 mL). To the mixture was added magnesium (27.4 g, 1.14 mol) batchwise when the reaction mixture was warmed at 40 °C. The resulting mixture was allowed to stir for 2 h at room temperature. The resulting mixture was concentrated under reduced pressure to remove MeOH. The residue was diluted with 500 mL of EtOAc and filtered.
  • Step 6 Into a 2 L 3 necked round bottomed flask was placed a solution of 5-[(4- methylphenyl)sulfonyl]-5,8-diazaspiro[2.6]nonane ethanedioate (50 g, 121.48 mmol, 90%) in DCM (800 mL) and Et 3 N (31 g, 310 mmol). To the mixture was added Boc 2 0 (26 g, 119 mmol) at 0-5 °C. The resulting solution was allowed to stir overnight at room temperature. The reaction mixture was washed with 3x500 mL of 3 ⁇ 40 and 1x500 mL of brine.
  • Step 7 Into a 3 L 3 necked round bottomed flask was placed a solution of fert-butyl 8-[(4- methylphenyl)sulfonyl]-5,8-diazaspiro[2.6]nonane-5-carboxylate (110 g, 232 mmol, 80%) in MeOH (1800 mL). To the mixture was added Mg (36 g, 1.50 mol) in several batches at 40 °C. The resulting solution was allowed to stir for 1 h at room temperature. The resulting mixture was concentrated under reduced pressure. The residue was diluted with 1 L of EtOAc and filtered. The filtrate was treated with a solution of oxalic acid in ether to precipitate the product.
  • Step 2 A mixture of 2-(methylthio)pyrrolo[2,l-
  • Step 3 Into a 100 mL round bottomed flask were added 2-(methylthio)pyrrolo[2,l-
  • Step 4 Into a 100 mL round bottom flask containing a solution of N-(3-(difluoromethyl)-l- methyl-lH-pyrazol-4-yl)-2-(methylthio)pyrrolo[2,l-
  • Step 5 A mixture of N-(3 -(dill uoromethyl)-l -methyl- lH-pyrazol-4-y l)-2- (methylsulfonyl)pyrrolo[2, l -
  • Step 6 Into a 10 mL round bottom flask containing a solution of fert-butyl ((15',2i?)-2-((7-((3- (difl uoromethyl)-l -methyl- lH-pyrazol-4-yl)carbamoyl)pyrrolo [2, 1-
  • fert-butyl ((15',2i?)-2-((7-((3- (difl uoromethyl)-l -methyl- lH-pyrazol-4-yl)carbamoyl)pyrrolo [2, 1-
  • reaction mixture was diluted with dichloromethane and washed with water and brine.
  • the organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressue.
  • the residue was purified by column chromatography eluting with methanol in dichloromethane (3-5%) to afford 7-bromo-2-(methylsulfinyl)pyrrolo[2,l-
  • Step 2 Into a 20 mL microwave vial containing a solution of 7-bromo-2- (methylsulfinyl)pyrrolo[2,l-
  • Step 3 Into a 25 mL clave containing a solution of fert-butyl ((15',2i?)-2-((7-bromopyrrolo[2,l-
  • fert-butyl ((15',2i?)-2-((7-bromopyrrolo[2,l-
  • Step 4 Into a 50 mL round bottom flask containing a solution of methyl 2-((( ⁇ R,2S)-2-((tert- butoxycarbonyl)amino)cyclohexyl)amino)pyrrolo[2, 1 -f] [1 ,2,4]triazine-7-carboxylate (700 mg, 1.8 mmol) in tetrahydrofuran (5 mL) and water (10 mL) was added lithium hydroxide (225 mg, 5.4 mmol) and the reaction was stirred at room temperature for 5 h. The reaction mixture was diluted with water and washed with ethyl acetate.
  • Step 5 Into a 10 mL round bottom flask containing a solution of 2-((( ⁇ R,2S)-2-((tert- butoxycarbonyl)amino)cyclohexyl)amino)pyrrolo[2, 1 -f] [1 ,2,4]triazine-7-carboxylic acid (40 mg, 0.1 mmol) in acetonitrile (2 mL) were added 1 -ethyl- lH-pyrazol-4-amine (20 mg, 0.12 mmol) and HATU (60 mg, 0.15 mmol) followed by the addition ofNN-diisopropylethylamine (0.03 mL, 0.2 mmol) and the reaction was stirred at 60 °C for 12 h.
  • Step 6 Into a 50 mL round bottom flask containing a solution of afford tert-butyl (( ⁇ S,2R)-2- ((7-(( 1 -ethyl- lH-pyrazol-4-y l)carbamoy l)pyrrolo [2, 1 -j ⁇ [ 1 ,2,4] triazin-2- yl)amino)cyclohexyl)carbamate (40 mg, 0.08 mmol) in 1,4-dioxane (0.5 mL) was added HC1 in dioxane (2 mL) and the reaction was stirred at room temperature of 1 h.
  • the kinase activity of IRAK4 is determined by its ability to catalyze the phosphorylation of a fluorescent polypeptide substrate.
  • the extent of phosphorylation is measured using the IMAP technology (Molecular Devices) where the phosphorylated fluorescent substrate binds to the large M(III)-based nanoparticles which reduces the rotational speed of the substrate and thus increases its fluorescent polarization (FP).
  • reaction mixture contains 10 mM TriHCl, pH 7.2, 0.5 nM GST tagged IRAK4 (SignalChem), 100 nM fluorescent peptide substrate (RP7030, Molecular Devices), 100 ⁇ ATP, 1 mM DDT, 1 mM MgCl 2 , and 0.01% Tween 20.
  • the reaction is initiated by the addition of ATP. After incubation for 30 minutes at 25 °C, 60 of Progressive IMAP Reagent (Molecular Devices) is added to stop the reaction. Change in RP7030's FP is determined by a FP reader (Analyst HT, LJL BioSystems).

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Abstract

La présente invention concerne des inhibiteurs de pyrrolotriazine d'IRAK 4 de formule I et des compositions comprenant ces inhibiteurs ainsi que des méthodes associées pour le traitement d'états pathologiques ou de maladies médié(e)s par IRAK 4 ou associé(e)s à IRAK 4.
PCT/US2016/021124 2015-03-12 2016-03-07 Inhibiteurs de pyrrolotriazine de l'activité d'irak4 WO2016144848A1 (fr)

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EP16762278.6A EP3268006B1 (fr) 2015-03-12 2016-03-07 Inhibiteurs de pyrrolotriazine de l'activité d'irak4
US15/557,203 US10329295B2 (en) 2015-03-12 2016-03-07 Pyrrolotriazine inhibitors of IRAK4 activity

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US9993514B2 (en) 2013-07-03 2018-06-12 Glaxosmithkline Intellectual Property Development Limited Compounds
US9604984B2 (en) 2014-05-23 2017-03-28 Genentech, Inc. 5-chloro-2-difluoromethoxyphenyl pyrazolopyrimidine compounds, compositions and methods of use thereof
US11434250B2 (en) 2016-11-02 2022-09-06 Genentech, Inc. Pyrazolo[1,5a]pyrimidine derivatives as IRAK4 modulators
US10307426B2 (en) 2017-05-22 2019-06-04 Genentech, Inc. Therapeutic compounds and compositions, and methods of use thereof
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WO2018234343A1 (fr) * 2017-06-21 2018-12-27 F. Hoffmann-La Roche Ag Benzofuranes utilisés en tant que modulateurs d'irak4
US10899774B2 (en) 2017-06-21 2021-01-26 Genentech, Inc. IRAK4 modulators
WO2018234342A1 (fr) * 2017-06-21 2018-12-27 F. Hoffmann-La Roche Ag Dérivés d'isoindolinone utilisés en tant que modulateurs d'irak4
CN110785418A (zh) * 2017-06-21 2020-02-11 豪夫迈·罗氏有限公司 作为irak4调节剂的异二氢吲哚酮衍生物
JP2020524692A (ja) * 2017-06-21 2020-08-20 エフ．ホフマン−ラ ロシュ アーゲーＦ． Ｈｏｆｆｍａｎｎ−Ｌａ Ｒｏｃｈｅ Ａｋｔｉｅｎｇｅｓｅｌｌｓｃｈａｆｔ Ｉｒａｋ４調節因子としてのベンゾフラン
JP2020524663A (ja) * 2017-06-21 2020-08-20 エフ．ホフマン−ラ ロシュ アーゲーＦ． Ｈｏｆｆｍａｎｎ−Ｌａ Ｒｏｃｈｅ Ａｋｔｉｅｎｇｅｓｅｌｌｓｃｈａｆｔ Ｉｒａｋ４調節因子としてのイソインドリノン誘導体
US11623932B2 (en) 2017-09-22 2023-04-11 Kymera Therapeutics, Inc. Protein degraders and uses thereof
US11358948B2 (en) 2017-09-22 2022-06-14 Kymera Therapeutics, Inc. CRBN ligands and uses thereof
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US12036209B2 (en) 2017-11-17 2024-07-16 Arvinas Operations, Inc. Compounds and methods for the targeted degradation of Interleukin-1 receptor-associated kinase 4 polypeptides
US11065231B2 (en) 2017-11-17 2021-07-20 Arvinas Operations, Inc. Compounds and methods for the targeted degradation of interleukin-1 receptor- associated kinase 4 polypeptides
WO2019111218A1 (fr) 2017-12-08 2019-06-13 Cadila Healthcare Limited Nouveaux composés hétérocycliques utilisés en tant qu'inhibiteurs d'irak4
US10874743B2 (en) 2017-12-26 2020-12-29 Kymera Therapeutics, Inc. IRAK degraders and uses thereof
US11318205B1 (en) 2017-12-26 2022-05-03 Kymera Therapeutics, Inc. IRAK degraders and uses thereof
WO2019133531A1 (fr) 2017-12-26 2019-07-04 Kymera Therapeutics, Inc. Agents de dégradation de kinases irak et leurs utilisations
US11723980B2 (en) 2017-12-26 2023-08-15 Kymera Therapeutics, Inc. IRAK degraders and uses thereof
US11932635B2 (en) 2018-01-12 2024-03-19 Kymera Therapeutics, Inc. CRBN ligands and uses thereof
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US11485743B2 (en) 2018-01-12 2022-11-01 Kymera Therapeutics, Inc. Protein degraders and uses thereof
US11512080B2 (en) 2018-01-12 2022-11-29 Kymera Therapeutics, Inc. CRBN ligands and uses thereof
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US11707457B2 (en) 2019-12-17 2023-07-25 Kymera Therapeutics, Inc. IRAK degraders and uses thereof
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US11779578B2 (en) 2019-12-17 2023-10-10 Kymera Therapeutics, Inc. IRAK degraders and uses thereof
US11685750B2 (en) 2020-06-03 2023-06-27 Kymera Therapeutics, Inc. Crystalline forms of IRAK degraders
US12097261B2 (en) 2021-05-07 2024-09-24 Kymera Therapeutics, Inc. CDK2 degraders and uses thereof
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EP3268006A1 (fr) 2018-01-17

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